KLF6 depletion promotes NF-κB signaling in glioblastoma

A. P. Masilamani, R. Ferrarese, E. Kling, N. K. Thudi, H. Kim, D. M. Scholtens, F. Dai, M. Hadler, T. Unterkircher, L. Platania, A. Weyerbrock, M. Prinz, G. Y. Gillespie, G. R. Harsh, M. Bredel, M. S. Carro

Research output: Contribution to journalArticlepeer-review

Abstract

Dysregulation of the NF-κB transcription factor occurs in many cancer types. Krüppel-like family of transcription factors (KLFs) regulate the expression of genes involved in cell proliferation, differentiation and survival. Here, we report a new mechanism of NF-κB activation in glioblastoma through depletion of the KLF6 tumor suppressor. We show that KLF6 transactivates multiple genes negatively controlling the NF-κB pathway and consequently reduces NF-κB nuclear localization and downregulates NF-κB targets. Reconstitution of KLF6 attenuates their malignant phenotype and induces neural-like differentiation and senescence, consistent with NF-κB pathway inhibition. KLF6 is heterozygously deleted in 74.5% of the analyzed glioblastomas and predicts unfavorable patient prognosis suggesting that haploinsufficiency is a clinically relevant means of evading KLF6-dependent regulation of NF-κB. Together, our study identifies a new mechanism by which KLF6 regulates NF-κB signaling, and how this mechanism is circumvented in glioblastoma through KLF6 loss.

Original languageEnglish (US)
Pages (from-to)3562-3575
Number of pages14
JournalOncogene
Volume36
Issue number25
DOIs
StatePublished - Jun 22 2017
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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